Phenazone (antipyrine)

Hematologic

Hemolysis can occur in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. An immediate reaction after a single test dose, in the form of latent leukopenia, has also been reported [ ], with previous sensitization to pyrazolone derivatives as the most probable explanation. Six women developed agranulocytosis after using a phenazone-containing cream [ ].

Gastrointestinal

Chronic abuse of phenazone, probably together with other more aggressive antipyretics, can cause gastric symptoms [ ].

Urinary tract

Phenazone nephrotoxicity is well-established. Experimental papillary necrosis can easily be provoked and analgesic nephropathy is probably a real danger with phenazone, especially when it is combined with a stronger inhibitor of prostaglandin synthesis. The effect is probably toxic, since inhibition of prostaglandins is not a marked characteristic of phenazone. Two reports have suggested a causal link between phenazone and renal carcinoma, as is well-known for phenacetin [ , ], but this has not been confirmed.

Skin

Urticarial rashes and erythema are the most common adverse reactions to phenazone, followed by maculopapular eruptions, erythema multiforme, erythema nodosum, or even angioedema [ ].

Erythema multiforme has been rarely reported with phenazone, but occurred in a 70-year-old man in association with a reticular exanthem after he used phenazone in combination with epirizole [ ].

General

Phenazone is an enzyme inducer and can increase the rate of metabolism of other drugs, including itself. Furthermore, since it is metabolized in the liver it is often used as a marker of hepatic drug metabolizing capacity [ , ]. In some cases it inhibits the metabolism of other drugs. Thus, there have been many studies of possible drug–drug interactions with phenazone, and many have proved negative. Drugs that have been shown to have no effect on phenazone kinetics include atorvastatin [ ], bromazepam [ ], cisapride [ ], conjugated estrogens [ ] (but see Hormonal contraceptives below), danaparoid [ ], encainide [ ], finasteride [ ], gabapentin [ ], hydrocortisone [ ], influenza vaccine [ ], josamycin [ ], lansoprazole [ ], lidocaine [ ], lithium [ ], mefloquine [ ], metronidazole [ ], misoprostol [ , ], nifedipine [ , ], nocloprost [ ], pantoprazole [ , ], pirenzepine [ ], propylene glycol [ ], ranitidine [ ], spiramycin [ , ], and terbutaline [ ].

Since phenazone is distributed in total body water, its apparent volume of distribution can be used to assess total body water.

Aminoglutethimide

In women with breast cancer, aminoglutethimide increased the clearance rates of phenazone by 81% [ ].

Aminophenazone (aminopyrine)

Aminopyrine 4.5 and 9 mg/kg prolonged the half-life and reduced the metabolic clearance of oral phenazone 18 mg/kg in healthy volunteers without changing its apparent volume of distribution; the disposition of aminophenazone was not changed [ ]. The authors concluded that phenazone and aminophenazone should not be administered simultaneously when studying different steps in hepatic drug oxidation.

Amiodarone

In one study amiodarone had no effect on the half-life of phenazone in 11 volunteers [ ]. However, in three patients amiodarone prolonged the half-life of phenazone by reducing its clearance [ ].

Ascorbic acid

In five healthy men ascorbic acid shortened the half-life of salivary phenazone, suggesting an increase in unbound clearance [ ].

Barbiturates

Barbiturates increase the clearance of phenazone by enzyme induction. For example, in seven healthy volunteers phenobarbital increased the total clearance of phenazone by 22% [ ] and in another study phenobarbital 180 mg/day for 3 weeks in 10 volunteers increased the clearance of phenazone by 90% [ ].

In four sets of identical and four sets of fraternal twins the half-life of phenazone after a single oral dose of 16 mg/kg was 13 hours and after administration of sodium phenobarbital 2 mg/kg/day for 2 weeks the half-life was shortened to 8 hours, with considerable interindividual variation [ ]. There were larger between-pair variances in the fraternal twins than in the identical twins.

Pentobarbital increased the clearance of phenazone by 60% and also increased the clearance of its main metabolites, 4-hydroxyphenazone, norphenazone, and 3-hydroxymethylphenazone + 3-carboxyphenazone, the largest effect being on norphenazone [ ].

Bepridil

Bepridil increases the rate of clearance of phenazone [ ].